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Abstract
Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches.
Dopamine regulates multiple brain functions through coexisting tonic and phasic release modalities. Here, the authors describe an approach for monitoring tonic and phasic dopamine release simultaneously via on-demand chemogenetic tuning of a dopamine sensor.
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1 University of Zürich, Institute of Pharmacology and Toxicology, Zürich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650); University and ETH Zürich, Neuroscience Center Zurich, Zürich, Switzerland (GRID:grid.5801.c) (ISNI:0000 0001 2156 2780); ETH Zürich, Department of Health Sciences and Technology, Zürich, Switzerland (GRID:grid.5801.c) (ISNI:0000 0001 2156 2780)
2 University of Zürich, Institute of Pharmacology and Toxicology, Zürich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650); ETH Zurich, Institute for Neuroscience, Zurich, Switzerland (GRID:grid.5801.c) (ISNI:0000 0001 2156 2780)
3 University of Zürich, Institute of Pharmacology and Toxicology, Zürich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650)
4 University of Colorado School of Medicine, Department of Pharmacology, Aurora, USA (GRID:grid.499234.1) (ISNI:0000 0004 0433 9255)
5 Université de Montréal, Department of Pharmacology & Physiology, Faculty of Medicine, SNC and CIRCA Research groups, Montréal, Canada (GRID:grid.14848.31) (ISNI:0000 0001 2104 2136); Université de Montréal, Department of Neurosciences, Faculty of Medicine, SNC and CIRCA Research groups, Montréal, Canada (GRID:grid.14848.31) (ISNI:0000 0001 2104 2136)
6 ETH Zürich, Department of Health Sciences and Technology, Zürich, Switzerland (GRID:grid.5801.c) (ISNI:0000 0001 2156 2780)
7 Istituto Italiano di Tecnologia, Optical Approaches to Brain Function Laboratory, Genova, Italy (GRID:grid.25786.3e) (ISNI:0000 0004 1764 2907)
8 University of Strasbourg, Institute of Cellular and Integrative Neuroscience, Strasbourg, France (GRID:grid.11843.3f) (ISNI:0000 0001 2157 9291)
9 University of Zürich, Institute of Pharmacology and Toxicology, Zürich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650); University and ETH Zürich, Neuroscience Center Zurich, Zürich, Switzerland (GRID:grid.5801.c) (ISNI:0000 0001 2156 2780)
10 Eli Lilly and Company, Indianapolis, USA (GRID:grid.417540.3) (ISNI:0000 0000 2220 2544)